Acute Acalculous Cholecystitis: a Rare Presentation of Autoimmune Hepatitis and Primary Sclerosing Cholangitis Overlap Syndrome

Case Report J Med Cases. 2018;9(10):332-337

Acute Acalculous Cholecystitis: A Rare Presentation of Autoimmune Hepatitis and Primary Sclerosing Cholangitis Overlap Syndrome

Feng Yina, Peter V. Draganovb, Jinping Laia, Steven J. Hughesc, Roberto J. Firpi-Morellb, Xiuli Liua, d

Abstract described in patients with primary sclerosing cholangitis [1- 4]. Histologically, gallbladder with LPC has a triad of find- Lymphoplasmacytic cholecystitis (LPC) is a unique form of chronic ings including diffuse chronic inflammatory infiltrate, a pre- cholecystitis, and it has been reported in patients with medical con- dominance of plasma cells in the lamina propria, and mucosal ditions such as primary sclerosing cholangitis, inflammatory bowel nodular lymphoid aggregate with occasional germinal center disease, and autoimmune pancreatitis. We report a case of LPC in a formation. An association of LPC with other forms of chronic 23-year-old male with a history of autoimmune hepatitis who pre- pancreatobiliary disease, including neoplastic obstruction and sented to the hospital with 3-day duration of abdominal pain, nau- autoimmune pancreatitis, has also been suggested [5-7]. In sea and vomiting. A clinical diagnosis of acute cholecystitis and one recent study, LPC could occur as sporadic cases in older sclerosing cholangitis was made, and the patient was treated with men and presented with typical signs and symptoms of acute laparoscopic cholecystectomy. Histopathological examination of cholecystitis such as fevers and/or leukocytosis [4]. LPC in the gallbladder revealed marked diffuse mononuclear inflammatory patients with inflammatory bowel disease has been reported infiltrate that was rich in IgG4-positive plasma cells and focal neu- [8]. trophilic inflammation with erosion. These findings were consistent “Autoimmune cholecystitis” is probably an alternative with active LPC. The patient’s post-operative endoscopic retrograde term in the literature for some chronic cholecystitis morpho- cholangiopancreatography performed 1 month after cholecystecto- logically resembling LPC. One study reported its association my revealed typical features of primary sclerosing cholangitis. This with autoimmune hepatitis and autoimmune pancreatitis [9]. In is the first report of acute acalculous cholecystitis as an initial pres- that case report, the patient experienced chronic vague abdom- entation of autoimmune hepatitis and primary sclerosing cholangitis inal pain, dark urine, acholic stools, and jaundice. Laboratory overlap syndrome. studies revealed elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase Keywords: Lymphoplasmacytic cholecystitis; Autoimmune hepati- (GGT), direct bilirubin, positive anti-nuclear antibody (ANA), tis; Primary sclerosing cholangitis; Overlap syndrome; IgG4 positive anti-smooth muscle antibody (ASMA), elevated IgG (4,080 mg/dL), and elevated lipase. Abdominal magnetic reso- nance imaging (MRI) revealed biliary duct dilatation with unremarkable pancreas. The patient had a liver biopsy show- Introduction ing chronic active hepatitis with mononuclear cell infiltrate and conspicuous plasma cells, features of autoimmune hepatitis. The portal inflammation relatively spared intrahepatic Lymphoplasmacytic cholecystitis (LPC) is an acalculous bile ducts. There was periductal inflammation but no obvious chronic inflammatory disease of gallbladder that was initially cholangitis, cholestasis or periductal fibrosis was seen. Histo- pathological examination of the gallbladder revealed features of LPC. Increased IgG4-positive plasma cells were noted in Manuscript submitted July 31, 2018, accepted August 24, 2018 both liver biopsy and gallbladder; though the exact number of aDepartment of Pathology, Immunology and Laboratory Medicine, College of IgG4-positive plasma cells were not given in the report. The Medicine, University of Florida, Gainesville, FL, USA patient responded well with steroid and 6-mercaptopurine bDepartment of Gastroenterology, Hepatology and Nutrition, College of Medi- treatment after cholecystectomy, which led to normalization cine, University of Florida, Gainesville, FL, USA of his transaminases and lipase levels. In the report, autoim- cDepartment of Surgery, College of Medicine, University of Florida, Gaines- mune cholecystitis is thought to be the biliary manifestation ville, FL, USA of a multisystem fibroinflammatory disorder. However the dCorresponding Author: Xiuli Liu, Department of Pathology, Immunology and Laboratory Medicine, P.O. Box 100275, Gainesville, FL 32610, USA. association of LPC with autoimmune hepatitis alone has not Email: [email protected] been reported in the literature. Herein, in this case report, we describe one case of LPC developed 9 years after the initial doi: https://doi.org/10.14740/jmc3137w diagnosis of autoimmune hepatitis and with a discussion of its

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Table 1. Laboratory Tests (Admitted in October 2017)

Reference range 1/16/2017 3/31/2017 6/23/2017 10/1/2017 2/13/2018 Total protein 6.1 - 8.1 g/dL 7.6 7.7 8.5 (H) 8.3 (H) 7.4 Albumin 3.5 - 5.2 g/dL 4.4 4.4 4.8 4.2 4.2 AST 0 - 37 IU/L 86 (H) 51 (H) 66 (H) 113 (H) 42 (H) ALT 0 - 50 IU/L 64 (H) 45 65 (H) 78 (H) 54 (H) Direct bilirubin 0.0 - 0.2 mg/dL 0.2 0.6 (H) 0.4 (H) 6.2 (H) Indirect bilirubin 0.2 - 1.2 mg/dL 0.5 1.5 (H) 0.9 Total bilirubin 0.0 - 1.0 mg/dL 0.7 2.1 (H) 1.3 (H) 10.2 (H) 1.4 (H) Alkaline phosphatase 40 - 150 IU/L 286 (H) 254 (H) 315 (H) 466 (H) 254 (H) Lipase 0 - 70 U/L 9 IgG 635 - 1,616 mg/dL 1,647 (H) IgM 45 - 281 mg/dL 186 ANA titer Negative 0.09722 Anti smooth muscle antibody Negative Negative Liver kidney microsomal antibody < 1:20 < 1:20 Tissue transglutaminase (TTG) IgA 0 - 3 U/mL 1

H: high. clinical significance. total protein at 8.3 g/dL. ANA was positive at 1:80. IgG was slightly elevated at 1,647 mg/dL (reference: 635 – 1,616 mg/ dL) (Table 1). Serum IgG4 was not tested on admission. Case Report Several imaging studies on admission were performed. Right upper quadrant ultrasound revealed distended gallblad- The patient is a 23-year-old man with a past medical history der with small sludge (Fig. 1a). The liver was echogenic and significant for autoimmune hepatitis diagnosed 9 years ago demonstrated beam attenuation consistent with fatty liver dis- that was based on clinical presentation, laboratory results and ease. There were no focal masses. The portal veins were non- liver biopsy in an outside hospital. The patient was initially dilated and demonstrated hepatopetal flow. The common bile treated with corticosteroids with episodes of relapse when duct was prominent and measured 6 mm in diameter. There’s weaning the prednisone. The patient was later started on Imu- no evidence of focal obstruction. The sonographic Murphy ran. Over the 9 years, he has had three liver biopsies with the sign was equivocal due to pain medication. Computed to- most recent one done in October of 2016 revealing stage 1 mography (CT) of the abdomen and pelvis with intravenous fibrosis and mild steatosis, without significant ongoing auto- contrast revealed unremarkable liver without intrahepatic frac- immune hepatitis. IgG4 level was within normal range. The ture pattern or biliary duct dilatation. The common bile duct patient is currently on Imuran (200 mg/day), Prograf (2 mg/ appeared enhancing, suspicious for cholangitis (Fig. 1b). The day), prednisone (7.5 mg/day), and Ursodiol (600 mg/day). gallbladder was markedly dilated with thickened wall. There The patient is also an alpha-1 antitrypsin (A1AT) deficiency was no definite pericholecystic fluid. A cholescintigraphy and carrier, MZ phenotype. Since his last liver biopsy, the patient hepatobiliary scintigraphy (HIDA) scan showed no filling of has had steadily increase in his alkaline phosphatase (ALP), the gallbladder which was consistent with acute cholecysti- transaminases AST and ALT, and total bilirubin (Table 1). He tis (Fig. 1c). Magnetic retrograde cholangiopancreatography also has a 14-pound weight loss in the past 10 months. (MRCP) plus pancreas without and with intravenous contrast The patient presented to our hospital for 3-day duration revealed dilated gallbladder with mild associated stranding of abdominal pain, nausea and vomiting and was admitted. concerning for acute cholecystitis (Fig. 1c). No choledocho- His abdominal pain got worse after he ate. He denied diar- lithiasis or dilation of common bile duct or pancreatic duct was rhea, jaundice, itching, icterus, fever, chills, or sweats. Review noted on MRCP. of his systems was not remarkable. On physical examination, The patient was diagnosed with cholecystitis and scle- he had soft abdomen without distension, masses, or ascites. rosing cholangitis and initially treated with Zofran and fluid Tenderness to palpation in upper quadrants and epigastric area bolus for 4 days. Laparoscopic cholecystectomy was then per- was present. He had normal bowel sounds. Laboratory studies formed. Intraoperative cholangiography revealed that the com- on admission revealed normal electrolytes, blood glucose, and mon bile duct appeared atretic with “moth-eaten” appearance renal function tests. His liver function test revealed ALT at 78 but without dominant stricture (Fig. 1d). IU/L, AST at 113 IU/L, ALP at 466 IU/L, total bilirubin at 10.2 The cholecystectomy specimen consisted of an opened mg/dL, direct bilirubin at 6.2 mg/dL, albumin at 4.2 g/dL, and gallbladder with scattered areas of red-brown punctate hemor-

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Figure 1. Preoperative and intraoperative imaging study of the gallbladder. (a) Right upper quadrant ultrasound showing distended gallbladder. (b) CT of the abdomen showing enhancing common bile duct. (c) Left: HIDA biliary study revealing no filling of the gallbladder. Right: MRCP demonstrating dilated gallbladder and mild associated stranding concerning for acute cholecystitis. (d) Intraoperative cholangiography revealing atretic common bile duct with moth-eaten appearance, features concerning for cholangitis. rhage on the outer surface. The cystic duct measured 0.7 cm in ated cholangitis in the remaining extrahepatic bile ducts. length and has a diameter of 0.6 cm. No calculi were identified The patient’s symptoms including abdominal pain, nau- in the gallbladder. The mucosal surface was pink-tan to pale- sea and vomiting were improved postoperatively and was dis- yellow with no distinct masses or lesions grossly identified. charged on the second postoperative day. The patient’s post- There was diffuse thickening of the gallbladder wall (0.4 - 0.9 operative ERCR revealed features consistent with primary cm). Histologically, all sections of the gallbladder revealed sclerosing cholangitis including segmental strictures such as a marked diffuse mononuclear inflammatory infiltrate that was hilar stricture and a dominant stricture at the left main duct, a plasma cell-rich (Fig. 2a, b). Focal neutrophilic inflammation chain of lakes appearance and diffuse attenuation of the intra- with erosion was present. Focally prominent lymphoid ag- hepatic bile ducts (Fig. 3). Biliary brushing cytology revealed gregates were noted in the mucosa. Epithelial hyperplasia and ductal cells and reactive atypia without evidence of malignan- multifocal intestinal metaplasia were present (Fig. 2c). The cy. At 3 months post-operative follow-up, the patient was do- chronic cholecystitis involved the cyst duct resection margin. ing well and his ALT, AST, total bilirubin, and ALP improved No granulomas, dysplasia, cholelithiasis, storiform fibrosis, or significantly although not completely normalized (Table 1). obliterative phlebitis were identified. Immunohistochemistry for IgG4 and IgG was performed, which revealed the presence of 25 - 60 IgG4-positive plasma cells per high power field Discussion but the ratio of IgG4 to IgG positive cells was 0.2 (Fig. 2d). A diagnosis of LPC was made based on the histology and an LPC is a unique form of chronic cholecystitis characterized increased number of IgG4-positive plasma cells. In addition, by the presence of diffuse plasma cells-rich mononuclear in- to differentiate IgG4-related sclerosing cholangitis versus pri- flammatory infiltrate and prominent lamina propria lymphoid mary sclerosing cholangitis, recommendations to check serum aggregate. Gallstones are usually absent. LPC has been report- IgG4 level and to perform endoscopic retrograde cholangio- ed in patients with inflammatory bowel disease [8], primary pancreatography (ERCP) were made to assess immune-medi- sclerosing cholangitis [1-4], and autoimmune pancreatitis [5-

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Figure 2. Histologic features of cholecystectomy. (a) Diffuse transmural mononuclear inflammatory infiltrate (H&E stain, 40 ×). (b) The plasma cell-rich mononuclear inflammatory infiltrate (H&E stain, 200 ×). (c) Left: Prominent lymphoid aggregates in the lamina propria (H&E stain, 100 ×). Right: The epithelium shows hyperplasia and focal intestinal metaplasia but negative for dysplasia (H&E stain, 400 ×). (d) Left: Increased number of IgG4 positive cells (immunostain, 400 ×). Right: IgG positive cell infiltrate in the wall (immunostain, 400 ×). The ratio of IgG4 to IgG positive cells in the photographed area was 0.2.

7]. Recently LPC was reported as sporadic cases in old man who presented with fever and/or leukocytosis. A rare case of autoimmune cholecystitis with histology resembling LPC was reported in a patient with systemic autoimmune disease (autoimmune hepatitis/cholangitis and autoimmune pancreatitis) [9]. But LPC in patient with autoimmune hepatitis alone has not been reported. Our case is unique. Clinically, the patient had symptoms of acute cholecystitis with 3-day duration of abdominal pain, nausea and vomiting. Eating aggravated the abdominal pain. The imaging studies including ultrasound, HIDA biliary scan, and abdominal CT revealed dilated gallbladder without evidence of choledocholiathiasis. The common bile duct was prominent on ultrasound and showed enhancement on CT imaging but no stricture noted; intrahepatic ducts were not dilated. His pancreas was normal. Intraoperative cholangiography revealed moth-eaten appearance for the common bile duct. Macroscopic examination of his gallbladder revealed diffuse wall thickening (0.4 to 0.9 cm). No gallstones or mass lesions were identified. No stricture was noted for the cystic duct. The serosa was smooth and glistening. All sections of the gallbladder showed typical features of LPC. But diagnostic features of Figure 3. ERCR performed 1 month after cholecystectomy revealing a hilar stricture and a dominant stricture at the left main duct, a chain of classic IgG4-related autoimmune cholecystitis, i.e., storiform lakes appearance and diffuse attenuation of the intrahepatic bile ducts, fibrosis and obliterating phlebitis, were not present. Immuno- features of primary sclerosing cholangitis. histochemistry revealed the presence of up to 60 IgG4 posi-

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Figure 4. Histopathological examination of previous liver biopsy (October 2016) showing features suggestive of biliary flow impairment. (a) Portal lymphocytic inflammation, bile duct injury, portal fibrosis, and edema (H&E stain, 200 ×). (b) Lobular neutrophilic inflammation with associated hepatocyte apoptosis in addition to mild steatosis (H&E stain, 400 ×). (c) Portal ductular proliferation, portal fibrosis and edema, and periportal hepatocyte rosette formation (H&E stain, 400 ×). (d) Stellate portal fibrosis (trichrome stain, 100 ×). tive plasma cells per high power field, but the ratio of IgG4 to after cholecystectomy confirmed the diagnosis of primary scle- IgG-positive cells was 0.2. In addition, multifocal intestinal rosing cholangitis. In the context of previous history of auto- metaplasia was noted, which indicated a chronic process and immune hepatitis, the patient’s currently liver disease fits best was corresponding to the patient’s increased ALP and biliru- with autoimmune hepatitis and primary sclerosing cholangitis bin in the past 10 months prior to the current acute presenta- overlap syndrome. This is the first case report for acute acal- tion. The discrepancy between acute clinical presentation and culous cholecystitis as the initial presentation of autoimmune chronic histological changes is similar to a recent report for hepatitis and primary sclerosing cholangitis overlap syndrome. this entity [4]. No dysplasia was identified in the gallbladder Our case report has several limitations. First, even though despite extensive sampling in our case. However the presence no gallstones were identified by imaging or by macroscopic of gallbladder intestinal metaplasia has been associated with examination of the gallbladder, this did not completely rule out increased risk for gallbladder cancer [10]. cholelithiasis-associated cholecystitis as the gallstones may In the current case, the chronic inflammatory process ex- have passed out of the body through the intestines. Second, tended to the resection margin of the cystic duct. The fact that the presence of up to 60 IgG4-positive plasma cells per high the patient had elevated ALP 1 year prior to the current admis- power field in the gallbladder wall suggests an IgG4-related sion raised a possibility that the current cholecystitis may be an cholecystitis, but the ratio of IgG4 to IgG-positive cells were extension or manifestation of primary sclerosing cholangitis. only 0.2 and serum IgG4 testing was not performed, thus this Retrospective review of previous liver biopsy from October suspicion cannot be confirmed further. Third, the patient has 2016 (1 year prior to the presentation) revealed portal lym- not had colonoscopy yet and thus whether his LPC was related phocytic inflammation, bile duct injury, ductular proliferation, to idiopathic inflammatory bowel disease remained unclear at portal fibrosis, edema, lobular neutrophilic inflammation, and the time being. periportal hepatocyte resetting, subtle features of biliary ob- In summary, we reported a case of LPC in a young adult struction (Fig. 4). The impression of cholangitis was further patient developed 9 years after the initial diagnosis of auto- supported by radiological studies. ERCP performed 1 month immune hepatitis. The diagnosis of LPC in this case prompt-

336 Articles © The authors | Journal compilation © J Med Cases and Elmer Press Inc™ | www.journalmc.org Yin et al J Med Cases. 2018;9(10):332-337 ed additional confirmatory study of the remaining bile duct; in patients with primary sclerosing cholangitis. J Hepatol. ERCP performed 1 month after cholecystectomy confirmed 2008;48(4):598-605. that the patient had primary sclerosing cholangitis. With all 4. Hammer ST, Appelman HD. Sporadic lymphoplasma- the available information, the patient’s current liver disease cytic cholecystitis: a clinicopathologic entity. Am J Clin fits best with an overlap syndrome (autoimmune hepatitis with Pathol. 2014;142(2):209-212. primary sclerosing cholangitis). This case report highlights the 5. Abraham SC, Cruz-Correa M, Argani P, Furth EE, Hru- significance of LPC recognition by pathologist in young pa- ban RH, Boitnott JK. Diffuse lymphoplasmacytic chronic tients with autoimmune hepatitis. Large studies are needed to cholecystitis is highly specific for extrahepatic biliary examine the prevalence of LPC in young patients with primary tract disease but does not distinguish between primary sclerosing cholangitis, as well as its predictive value. and secondary sclerosing cholangiopathy. Am J Surg Pathol. 2003;27(10):1313-1320. 6. Abraham SC, Cruz-Correa M, Argani P, Furth EE, Hru- Conflict of Interest ban RH, Boitnott JK. Lymphoplasmacytic chronic cholecystitis and biliary tract disease in patients with lymphop- None. lasmacytic sclerosing pancreatitis. Am J Surg Pathol. 2003;27(4):441-451. 7. Wang WL, Farris AB, Lauwers GY, Deshpande V. Au- Grant Support toimmune pancreatitis-related cholecystitis: a morpho- logically and immunologically distinctive form of lym- None. phoplasmacytic sclerosing cholecystitis. Histopathology. 2009;54(7):829-836. 8. Lin J, Shen B, Lee HJ, Goldblum JR. Histopathological References characterization of cholecystectomy specimens in patients with inflammatory bowel disease. J Crohns Colitis. 1. Jessurun J, Bolio-Solis A, Manivel JC. Diffuse lymphop- 2012;6(9):895-899. lasmacytic acalculous cholecystitis: a distinctive form of 9. Memon Z, Moya DA, Baker R, Kozielski R, Baker S. chronic cholecystitis associated with primary sclerosing Autoimmune cholecystitis. J Pediatr Gastroenterol Nutr. cholangitis. Hum Pathol. 1998;29(5):512-517. 2012;54(4):441. 2. Kamisawa T, Tu Y, Nakajima H, Egawa N, Tsuruta K, 10. Lewis JT, Talwalkar JA, Rosen CB, Smyrk TC, Abraham Okamoto A, Horiguchi S. Sclerosing cholecystitis asso- SC. Prevalence and risk factors for gallbladder neopla- ciated with autoimmune pancreatitis. World J Gastroen- sia in patients with primary sclerosing cholangitis: evi- terol. 2006;12(23):3736-3739. dence for a metaplasia-dysplasia-carcinoma sequence. 3. Said K, Glaumann H, Bergquist A. Gallbladder disease Am J Surg Pathol. 2007;31(6):907-913.